BackgroundLung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.Methodology/Principal FindingsThe LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.Conclusions/ SignificanceThe lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

Background Identifying strong markers of prognosis is critical to optimize treatment and survival outcomes in patients with non-small cell lung cancer (NSCLC). We investigated the prognostic significance of preoperative cardiorespiratory fitness (VO2peak) among operable candidates with NSCLC. Methods Using a prospective design, 398 patients with potentially resectable NSCLC enrolled in Cancer and Leukemia Group B (CALGB) 9238 were recruited between 1993 and 1998. Participants performed a cardiopulmonary exercise test to assess VO2peak and were observed for death or until June 2008. Cox proportional models were used to estimate the risk of all-cause mortality according to cardiorespiratory fitness category defined by VO2peak tertiles (<0.96 / 0.96–1.29 / >1.29 L.min−1) with adjustment for age, gender, performance status. Results Median follow-up was 30.8 months, 294 deaths were reported during this period. Compared with patients achieving a VO2peak <0.96 L.min−1, the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% CI, 0.46 to 0.88) for a VO2peak of 0.96–1.29 L.min−1, and 0.56 (95% CI, 0.39 to 0.80) for a VO2peak of >1.29 L.min−1 (ptrend= 0.0037). The corresponding HRs for resected patients were 0.66 (95% CI, 0.46 to 0.95) and 0.59 (95% CI, 0.40 to 0.89) relative to the lowest VO2peak category (ptrend=0.0247), respectively. For non-resected patients, the HRs were 0.78 (95% CI, 0.34 to 1.79) and 0.39 (95% CI, 0.16 to 0.94) relative to the lowest category (ptrend=0.0278). Conclusions VO2peak is a strong independent predictor of survival in NSCLC that may complement traditional markers of prognosis to improve risk stratification and prognostication.

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